5ikv: Difference between revisions
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==The Structure of Flufenamic Acid Bound to Human Cyclooxygenase-2== | ==The Structure of Flufenamic Acid Bound to Human Cyclooxygenase-2== | ||
<StructureSection load='5ikv' size='340' side='right' caption='[[5ikv]], [[Resolution|resolution]] 2.51Å' scene=''> | <StructureSection load='5ikv' size='340' side='right'caption='[[5ikv]], [[Resolution|resolution]] 2.51Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5ikv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IKV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IKV FirstGlance]. <br> | <table><tr><td colspan='2'>[[5ikv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IKV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IKV FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=COH:PROTOPORPHYRIN+IX+CONTAINING+CO'>COH</scene>, <scene name='pdbligand=FLF:2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO]+BENZOIC+ACID'>FLF</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=COH:PROTOPORPHYRIN+IX+CONTAINING+CO'>COH</scene>, <scene name='pdbligand=FLF:2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO]+BENZOIC+ACID'>FLF</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ikr|5ikr]], [[5ikq|5ikq]], [[5ikt|5ikt]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ikr|5ikr]], [[5ikq|5ikq]], [[5ikt|5ikt]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTGS2, COX2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ikv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ikv OCA], [http://pdbe.org/5ikv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ikv RCSB], [http://www.ebi.ac.uk/pdbsum/5ikv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ikv ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ikv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ikv OCA], [http://pdbe.org/5ikv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ikv RCSB], [http://www.ebi.ac.uk/pdbsum/5ikv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ikv ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 5ikv" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5ikv" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Prostaglandin-endoperoxide synthase]] | [[Category: Prostaglandin-endoperoxide synthase]] | ||
[[Category: Malkowski, M G]] | [[Category: Malkowski, M G]] | ||
Revision as of 14:50, 25 December 2019
The Structure of Flufenamic Acid Bound to Human Cyclooxygenase-2The Structure of Flufenamic Acid Bound to Human Cyclooxygenase-2
Structural highlights
Function[PGH2_HUMAN] Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.[1] Publication Abstract from PubMedCyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid (AA) and endocannabinoid substrates, placing the enzyme at a unique junction between the eicosanoid and endocannabinoid signaling pathways. COX-2 is a sequence homodimer, but the enzyme displays half-of-sites reactivity, such that only one monomer of the dimer is active at a given time. Certain rapid reversible, competitive nonsterroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit COX-2 in a substrate-selective manner, with the binding of inhibitor to a single monomer sufficient to inhibit the oxygenation of endocannabinoids, but not AA. The underlying mechanism responsible for substrate-selective inhibition has remained elusive. We utilized structural and biophysical methods to evaluate flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid for their ability to act as substrate-selective inhibitors. Crystal structures of each drug in complex with human COX-2 revealed that the inhibitor binds within the cyclooxygenase channel in an inverted orientation, with the carboxylate group interacting with Tyr-385 and Ser-530 at the top of the channel. Tryptophan fluorescence quenching, continuous-wave electron spin resonance, and UV/Vis spectroscopy demonstrate that flufenamic acid, mefenamic acid, and tolfenamic acid are substrate-selective inhibitors that bind rapidly to COX-2, quench tyrosyl radicals, and reduce higher oxidation states of the heme moiety. Substrate-selective inhibition was attenuated by the addition of the lipid peroxide 15-hydroperoxyeicosatertaenoic acid. Collectively, these studies implicate peroxide tone as an important mechanistic component of substrate-selective inhibition by flufenamic acid, mefenamic acid, and tolfenamic acid. Substrate Selective Inhibition of Cyclooxygenase-2 by Fenamic Acid Derivatives is Dependent on Peroxide Tone.,Orlando BJ, Malkowski MG J Biol Chem. 2016 May 20. pii: jbc.M116.725713. PMID:27226593[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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